Several O-alkyl derivatives of macrolide and azalide antibiotics have been described in the literature. Among them O-methyl derivatives of erythromycin (clarithromycin) (U.S. Pat. No. 4,331,803) and azithromycin (U.S. Pat. No. 5,250,518) have significant biological activity. The process for preparing O-alkyl derivatives of macrolides and azalides is typically a multistep procedure. Because macrolide and azalide compounds posses several hydroxyl groups it has previously been difficult to alkylate one hydroxyl group selectively in the presence of other unprotected hydroxyl or amino groups (see e.g. J. Antibiot. 46 (1993) 647, 1239; J. Antibiot. 43 (1990) 286). In order to carry out selective O-alkylation of macrolides and azalides, the use of various protecting groups has been described in the literature (see e.g. J. Antibiot. 45 (1992) 527, J. Antibiot. 37 (1984) 187, J. Antibiot. 46 (1993) 1163, U.S. Pat. Nos. 5,872,229; 5,719,272and 5,929,219). Specifically, the multistep selective synthesis of 12-O-methyl azithromycin has been described in WO 99/20639. However, the selective substitution at the 11-O-position with alkyl group is not easily accomplished by prior art methods and is accompanied by side reactions, by-products and low yields.
Generally, the classical method for O-methylation of macrolides and azalides proceedes by initial protection of the reactive sites on the desosamine, typically as 2′-OCbz-3′NMeCbz. Such protected derivative is then O-methylated in a dipolar aprotic solvent (e.g. DMSO/THF or DMF) using a base (e.g. KOH or NaH) and methyl iodide. Removal of the Cbz's and Eschwiler-Clarke methylation of the 3′-nitrogen completes the sequence. It should be noted that there are four hydroxyls that can be methylated (4″, 6, 11 and 12) and mixtures of various mono-, di- and tri-O-methylated derivatives are usually obtained.
Moreover, prior art investigations showed that (Bioorg.Med.Chem.Lett., 8 (1998)549) the relative reactivity of hydroxyl groups under the classical O-methylation reaction conditions proceeds in following order: for the 8a-azalides 4″-OH>12-OH>>11-OH, for 9a-azalides 11-OH≧12-OH>4″-OH. It is important to mention that under even the most vigorous reaction conditions O-methylation of 8a- and 9a-azalide 6-OH group does not occur. This is in contrast to the O-methylation of erythromycin in which system the 6-OH is easily methylated under conditions very similar to these (J.Antibiotics 43 (1990)286). However, in all cases mixtures of various mono-, and di- and tri-O-methylated derivatives are generally obtained. The relative rates of methylation of the hydroxyls presumably depend on subtle conformation details and are not predictable by a cursory inspection of the structure.
On the other hand substantially or partially regioselective, but not complete, regioselective methylation of various monosaccharides and nucleosides with diazomethane in the presence of transition-metal halides or boric acid has been described in the literature, [Carb.Res. 316 (1990) 187; Helv. Chim. Acta 79 (1996) 2114-2136; Chem.Pharm.Bull., 18 (1970) 677; Carb.Res., 91 (1981) 31], but it has not been possible to predict the site of methylation. Moreover, there are no known reports of regioselective O-alkylation of the 11-hydroxyl group of macrolides and azalides with diazoalkanes in the presence of transition-metal halides or boric acid
In connection with these reported observations, the exclusive (complete) regioselective 11-O-methylation by the process of the present invention is unique and not obvious.